IMMUNE-MEDIATED HEMOLYTIC ANEMIA

Overview
Immune-mediated hemolytic anemia (IMHA)is one of the more common autoimmune disorders that we see in canine patients as well as being one of the most common causes of anemia. Recognition of the disease is critical to allow for swift treatment to allow for the most favorable outcome as mortality can be high with these cases with varying rates of 29%-77%. The practitioner also needs to rule out other diseases and causes of anemia that may complicate the presentation and alter prognosis or therapy.

Pathophysiology
Tolerance by the immune system exists to prevent the destruction of the body’s own tissues. In the development of IMHA, anti-erythrocyte antibodies will collect on the red blood cell (RBC) membrane and the immune system will target them for removal. This removal is typically done by the mononuclear phagocyte system (MPS). In this circumstance, macrophages will remove the RBC causing extravascular hemolysis. Complement removal of RBC can also occur resulting in an intravascular hemolysis. Primary and secondary classifications of IMHA exist. Immune- mediated disease may be an idiopathic primary process or may be stimulated by concurrent diseases such as tick borne disease, neoplasia, recent vaccination, or certain medications such as cephalosporins and sulfa antibiotics. Drug related IMHA occurs when the drug particles attach to the RBC inciting the immune response, or by increasing levels of antibody production inciting the RBC removal by complement.  A complete history can help in identifying correlating causes for the development of IMHA.

There are several complications associated with canine IMHA. Approximately 50% of canine IMHA patients will develop concurrent thrombocytopenia resulting in Evan’s syndrome.3,7 Cases presenting with concurrent severe thrombocytopenia (platelets < 50,000) can be more intense to manage due to concurrent red cell loss from bleeding. Other commonly reported complications include thromboembolism (TE) and disseminated intravascular coagulopathy (DIC).

Signalment and presentation
IMHA has been reported to occur in certain breeds with increased frequency including Cocker Spaniel, Bichon Frise, and IOU. A higher incidence in the spring and summer months has been reported although a correlation with an infectious disease has not been documented. Patients may present with an acute onset of weakness, lethargy, and/ or decreased appetite or have a more chronic decline. On exam, it is common to find clinical evidence of anemia to include pale mucous membranes, tachycardia, heart murmur, and poor pulse quality. If thrombocytopenia is also present then petechiae, ecchymoses, melena, or bleeding from the nose or mouth may also be apparent.

Diagnosis
A full evaluation of the patient to include a CBC with reticulocyte count, chemistry profile, urinalysis, and screen for a rickettsial disease is advised. In addition, imaging of the chest and abdomen is also advised to evaluate for concurrent diseases such as neoplasia, infection, metallic foreign material, or inflammatory changes that one may see secondary to an immune mediated process.

With IMHA, patients typically will have a regenerative anemia with evidence of spherocytes upon evaluation of a blood smear. One may also see auto agglutination on a slide either macro or microscopically. A Coomb’s test may be useful in some patients that do not exhibit auto agglutination although a negative result does not rule out IMHA. Some cases may have a non-regenerative anemia either due to a very acute process or due to the immune-mediated attack of the red cell precursors at the level of the bone marrow. If a non-regenerative anemia is present or if there is anemia concurrent with a decrease in either the white blood cells or platelets then a bone marrow evaluation is recommended to evaluate for primary marrow disorders and neoplasia. Other common changes on screening diagnostics include hyperbilirubinemia, elevated liver values, and hemoglobinuria.

Treatment
Treatment of IMHA is directed at suppressing the immune response, treating any concurrent disease processes, and symptomatically supporting the patient. Blood transfusions are likely to be required in the majority of cases to maintain red cell concentration. However, patients may require multiple transfusions which increases the rate of transfusion reactions. Difficulty blood typing and cross matching these patients due to the presence of auto agglutination can also complicate the transfusion process. Given the high prevalence of rickettsial disease in this area, we will often recommend a course of doxycycline in patients that test negative for the more common diseases due to the concern for a peracute infection. Steroids remain the primary drug used for immunosuppressive therapy and prednisone therapy is started at 1-2mg/kg/day. We find that many patients benefit from the addition of a secondary agent to allow a lower dose of prednisone to minimize side effects and allow better control of the disease process. There are several agents available and the choice of which to use is often determined in part due to finances, available dosing with patient size, and concurrent disease processes.

The most common secondary agents include mycophenolate (12-20mg/kg/day), cyclosporine (Atopica) (5-10mg/kg/day), and azathioprine (2mg/kg/day for 7 days then every other day).  Mycophenolate is available in both injectable and oral forms although the former is quite expensive. In smaller dogs, the Mycophenolate may need to be compounded. Primary side effects include gastrointestinal upset with diarrhea being most common. Cyclosporine is preferably administered as a brand name due to increased bioavailability. This is often cost prohibitive in large dogs but may be a good option for dogs that are less than 30 pounds. Azathioprine is a cost effective option in larger dogs, however, may be contraindicated in patients with any known liver disease or current or historical pancreatitis. It may take up to seven days to see a response to any therapy, even in combination. This may be a limiting factor for some families due to the finances involved should a patient require more aggressive hospitalized care.

Thromboembolism (TE) has been identified in 60-80% of patients with IMHA and therefore therapy directed at prevention is indicated. There remains a lack of concrete evidence in the literature as to the best approach for preventing TE. Oral aspirin therapy (0.5mg/kg q 12hrs) and clopidogrel (1mg/kg/day) are used most commonly. Unfractionated heparin has also been evaluated both as intermittent injections or as a CRI and is largely limited to referral institutions. Human IVIg can also be considered for patients with a more refractory disease to slow the immune destruction of red blood cells. IVIg is a pool of human immunoglobulins (primarily IgG) that result in multiple immunomodulatory properties. While IVIg reduces immune destruction of red blood cells via multiple mechanisms, the primary mechanism is macrophage Fc receptor blockade. In doing so, the macrophage Fc receptors are occupied preventing antibody bound red blood cells from binding. While IVIg may be a beneficial adjunctive therapy in some canine IMHA patients, the current expense ($1,000–3,000/infusion) and lack of definitive evidence in the treatment of IMHA limit the use of this immunomodulatory agent.

Patients with IMHA will require long term drug therapy and monitoring to ensure long term remission and to minimize complications. The majority of patients will require 4-6 months of therapy with a gradual taper of medications performed every 2-4 weeks based upon monitoring of cell counts. Some patients may require long term or lifelong therapy depending on their response. There also remains a risk for relapse once drug therapy has been discontinued. Monitoring for drug related complications and occult infections is also imperative to ensuring long term success. With accurate diagnosis and therapy, discharge rates have been reported to be 50-80% among studies once initial control of the disease has been achieved.

Submitted by: Jennifer Bagshaw, DVM, DACVIM

References:

Carr, Anthony P., David L. Panciera, and Linda Kidd. “Prognostic factors for mortality and thromboembolism in canine immune‐mediated hemolytic anemia: A retrospective study of 72 dogs.” Journal of Veterinary Internal Medicine 16.5 (2002): 504-509.

Duval, Derek, and Urs Giger. “Vaccine‐associated immune‐mediated hemolytic anemia in the dog.” Journal of Veterinary Internal Medicine 10.5 (1996): 290-295. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.1996.tb02064.x/full

Klag, Alan R., U. Giger, and Frances S. Shofer. “Idiopathic immune-mediated hemolytic anemia in dogs: 42 cases (1986-1990).” JOURNAL-AMERICAN VETERINARY MEDICAL ASSOCIATION 202 (1993): 783-783. https://www.researchgate.net/profile/Urs_Giger3/publication/14743828_Idiopathic_immune-mediated_hemolytic_anemia_in_dogs_42_Cases_1986-1990/links/00b7d52e02baf90c30000000/Idiopathic-immune-mediated-hemolytic-anemia-in-dogs-42-Cases-1986-1990.pdf

Scott-Moncrieff, J. Catharine, et al. “Hemostatic abnormalities in dogs with primary immune-mediated hemolytic anemia.” Journal of the American Animal Hospital Association 37.3 (2001): 220-227.http://www.jaaha.org/doi/abs/10.5326/15473317-37-3-220

Grundy, Sophie A., and Claudia Barton. “Influence of drug treatment on survival of dogs with immune-mediated hemolytic anemia: 88 cases (1989–1999).” Journal of the American Veterinary Medical Association 218.4 (2001): 543-546.http://avmajournals.avma.org/doi/abs/10.2460/javma.2001.218.543

Weinkle, Tristan K., et al. “Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993–2002).” Journal of the American Veterinary Medical Association 226.11 (2005): 1869-1880 http://avmajournals.avma.org/doi/abs/10.2460/javma.2005.226.1869

Jackson, Marion L., and Stephen A. Kruth. “Immune-mediated Hemolytic Anemia and Thrombocytopenia in the Dog: A retrospective study of 55 cases diagnosed from 1979 through 1983 at the Western College of Veterinary Medicine.” The Canadian Veterinary Journal 26.8 (1985): 245.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1680025/

Klein, M. K., S. W. Dow, and R. A. Rosychuk. “Pulmonary thromboembolism associated with immune-mediated hemolytic anemia in dogs: ten cases (1982-1987).” Journal of the American Veterinary Medical Association 195.2 (1989): 246-250.http://europepmc.org/abstract/med/2768046

Piek, C. J., et al. “Idiopathic immune‐mediated hemolytic anemia: Treatment outcome and prognostic factors in 149 dogs.” Journal of Veterinary Internal Medicine 22.2 (2008): 366-373. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2008.0060.x/full

Reimer, Michele E., Gregory C. Troy, and Lorin D. Warnick. “Immune-mediated hemolytic anemia: 70 cases (1988-1996).” Journal of the American Animal Hospital Association 35.5 (1999): 384-391.http://www.jaaha.org/doi/abs/10.5326/15473317-35-5-384

Sinnott, Virginia B., and Cynthia M. Otto. “Use of thromboelastography in dogs with immune‐mediated hemolytic anemia: 39 cases (2000–2008).” Journal of veterinary emergency and critical care 19.5 (2009): 484-488.http://onlinelibrary.wiley.com/doi/10.1111/j.1476-4431.2009.00455.x/full

Scott-Moncrieff, J. C., et al. “Intravenous administration of human immune globulin in dogs with immune-mediated hemolytic anemia.” Journal of the American Veterinary Medical Association 210.11 (1997): 1623-1627.http://europepmc.org/abstract/med/9170090

Kellerman, Dana L., and David S. Bruyette. “Intravenous Human Immunoglobulin for the Treatment of Immune‐Mediated Hemolytic Anemia in 13 Dogs.” Journal of Veterinary Internal Medicine 11.6 (1997): 327-332.http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.1997.tb00475.x/full

Whelan, Megan F., et al. “Use of human immunoglobulin in addition to glucocorticoids for the initial treatment of dogs with immune‐mediated hemolytic anemia.” Journal of veterinary emergency and critical care 19.2 (2009): 158-164.http://onlinelibrary.wiley.com/doi/10.1111/j.1476-4431.2009.00403.x/full

Mellett, A. M., R. K. Nakamura, and D. Bianco. “A Prospective Study of Clopidogrel Therapy in Dogs with Primary Immune‐Mediated Hemolytic Anemia.” Journal of veterinary internal medicine 25.1 (2011): 71-75.http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2010.0656.x/full

Helmond, S. E., et al. “Treatment of immune‐mediated hemolytic anemia with individually adjusted heparin dosing in dogs.” Journal of veterinary internal medicine 24.3 (2010): 597-605. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2010.0505.x/full

Swann, J. W., and B. J. Skelly. “Systematic review of evidence relating to the treatment of immune‐mediated hemolytic anemia in dogs.” Journal of veterinary internal medicine 27.1 (2013): 1-9.
https://www.ncbi.nlm.nih.gov/pubmed/23279007

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